Both proliferative and CTL responses of patients with chronic HCV infections to peptide antigens and antigens expressed by recombinant DNA systems.Several CTL epitopes have been defined in the core protein, NS3,NS4 and NS5. CTL responses to these epitopes are being investigated in patients to understand the relationship of CTL to the pathogenesis of hepatitis C.It is important to know if these CTL responses are related to disease induction or to recovery from. A new HLA A2 restricted CTL epitope CTL epitpope was identified in the NS3 protein. This epitpoe was found by a novel technique that did not require synthesis of peptides nor prediction based on known A2 motifs. This epitope indeed was not a known A2 motif. Naked DNA vaccines expressing all the structural genes and the NS3 gene have been prepared and shown to be antigenic in mice. The hypervariable region has also been studied as a source of T cell epitopes ad a helper epitope has been identified in a relatively conserved region of the so called hypervariable region. This helper epitope may be important in regulating the immune response to that region. New approaches to in vitro neutralization are being studied including a binding assay for HCV envelope glycoproteins to cells, reduction in viral replication as measured by CTL assays usiing specific T cell lines and detection of intracellular HCV enzyme systems as a measure of HCV replication. Several of these assays should also be useful for antiviral screening. Hepatitis C is a major public health problem for which control is at a preliminary stage. CBER is actively involved in the licensing of new diagnostic tests that can be used to improve the screening of blood and source plasma. CBER ihas responsibility for biologic based therapeuticssuch as interferon. Experimental vaccines have already been described and the first IND's are expected shortly. Therapeutic vaccines based on CTL epitopes are also being actively pursued by several laboratories and companies. Understanding the immunobiology of hepatitis C has a direct relationship to the products that we have already licensed and are presently reviewing for screening blood and plasma products as well as therapeutics that have been licensed and are under review such as interferons. Again understanding the immunology of HCV infections and immunopathogenesis will be vitally important for our reviews of these projects.